Current Pharmaceutical Design, Volume 7, Number 6, 2001
Endocrine and Metabolic Agents
Executive Editors: Bruce D. Roth / Drago R. Sliskovic
Contents
Current
Therapies and Emerging Targets for the Treatment of Diabetes Pp. 417-450
The Immunomodulatory Effects
of Anti-thyroid Drugs are Mediated via Actions on Thyroid Cells, Affecting
Thyrocyte-immunocyte Signalling: A Review
Pp.
451-460
Prostaglandins and Lipid
Modification Pp. 461-474
[Back
to top] Current Therapies and
Emerging Targets for the Treatment of Diabetes
Allan S. Wagman and John
M. Nuss
Concurrent
with the spread of the western lifestyle, the prevalence of all types of diabetes
is on the rise in the world's population. The number of diabetics is increasing
by 4-5% per year with an estimated 40-45% of individual's over the age of 65
years having either type II diabetes or impaired glucose tolerance. Since the
signs of diabetes are not immediately obvious, diagnosis can be preceded by an
extended period of impaired glucose tolerance resulting in the prevalence of
beta-cell dysfunction and macrovascular complications. In addition to increased
medical vigilance, diabetes is being combated through aggressive treatment
directed at lowering circulating blood glucose and inhibiting postprandial
hyperglycemic spikes. Current strategies to treat diabetes include reducing
insulin resistance using glitazones, supplementing insulin supplies with
exogenous insulin, increasing endogenous insulin production with sulfonylureas
and meglitinides, reducing hepatic glucose production through
biguanides, and limiting postprandial glucose absorption with alpha-glucosidase
inhibitors. In all of these areas, new generations of small molecules are being
investigated which exhibit improved efficacy and safety profiles. Promising
biological targets are also emerging such as (1) insulin sensitizers including
protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3),
(2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH)
inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine
palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by
means of beta 3-adrenoceptor agonists. Also important are alternative routes of
glucose disposal such as Na + -glucose cotransporter (SGLT) inhibitors,
combination therapies, and the treatment of diabetic complications (eg.
retinopathy, nephropathy, and neuropathy). With may new opportunities for drug
discovery, the prospects are excellent for development of innovative therapies
to effectively manage diabetes and prevent its long term complications. This
review highlights recent (1997-2000) advances in diabetes therapy and research
with an emphasis on small molecule drug design (275 references).
[Back
to top] The Immunomodulatory Effects
of Anti-thyroid Drugs are Mediated via Actions on Thyroid Cells, Affecting
Thyrocyte-immunocyte Signalling: A Review
The mechanism of action of the immunosuppressive effects
of antithyroid drugs has remained a matter of controversy, despite our earlier
contention that such effects in vivo were indirect; ie., it was our view
that the drugs were acting on the thyroid cells, reducing their thyroid hormone
production and other activities, with a consequent reduction in
thyrocyte-immunocyte signalling. The reduction in the activation of CD4+
cells,the increased number and activation of CD8+ (and CD8+CDllb+) cells, and
the reduction of soluble interleukin-2 receptors, thought once to be direct
effects of the medication, are now shown to be due to amelioration of the
hyperthyroidism. Thus the reduction in thyroid hormone production induced by
the drugs is central to these actions. In addition, the iodination of
thyroglobulin is inhibited by these agents, which may affect antigen
presentation by the thyrocyte. Furthermore, there is now evidence that the
thionamides interfere with thyrocyte expression of such molecules as Class I
antigen, interleukin-1 , interleukin-6, prostaglandin E 2 , and heat shock protein. The expression of thyrocyte Class II
antigen is probably not inhibited by these drugs, although one group has shown
that lectin-stimulated thyrocyte Class II expression is diminished by this
treatment; this group postulated that this effect might be mediated by reduced
interferon gamma production by T lymphocytes, but in vitro experiments
do not corroborate this proposal. In any event, the actions as described of the
effects of antithyroid drugs on the thyroid cells (particularly normalization
of thyroid function) would certainly suffice to explain the diminution of
thyroid antibodies (including thyroid stimulating antibody), the reduced
immunological response, and the increased remission rate in Graves’ disease as
a consequence of antithyroid drug therapy, without the need to invoke a direct
immunosuppressive effect.
[Back
to top] Prostaglandins and Lipid Modification
Postaglandins(PG) and low-density lipoproteins (LDL) both
are playing a key role in atherogenesis. Their interaction at the local
vascular level is of central relevance in plaque formation and progression.
Details of these complex actions however, still need to be elucidated.
Lipoproteins are influencing the PG-production of arterial wall cells and
platelets, while PGs in turn have been shown to regulate lipoprotein receptor
binding and entry into the arterial wall. Modification of LDL severely
influences arterial wall trapping and foam cell formation. During
LDL-modification, isoprostanes, a new family of compounds generated by free
radical catalysed action, independent of cyclooxygenase, are formed. 8-epi PGF
2α the most well known member exerts a great variety of proatherogenic actions,
among them vasoconstriction and platelet activation; it also serves as a
mitogen and stimulator of endothelin release. The influence of various
eicosanoids on lipoprotein modification, however, has not been assessed yet.
[Back
to top] Pharmacology of Phosphoinositides,
Regulators of Multiple Cellular Functions
Tamas
Balla
Inositol phospholipids represent a small fraction of the phospholipids present in all cellular membranes with remarkable importance in regulating various cell functions. They are synthesized from phosphatidylinositol by sequential phosphorylations on the several hydroxyls of the inositol ring to create polyphos-phoinositides that function eith as docking sites to promote formation of molecular signaling complexes, or serve as precursors for soluble inositol polyphosphates that act as diffusible intracellular messengers. Phosphoinositides are involved in the control of many processes, including membrane traffic, endo- and exocytosis, mitogenesis and apoptosis. Pharmacological tools have helped to clarify many details of phosphoinositide metabolism and have unveiled the roles of these lipids in the control of specific signaling pathways. However, because of their pleiotropic functions it has been questionable whether pharmacological manipulation of inositide formation and metabolism can be of therapeutic value. This review briefly summarizes the means by which inositide functions have been pharmacologically manipulated, and discusses possibilities for specifically targeting certain aspects of their regulatory functions.